WO2010100252A1 - Method of dissolving antifungal agent, and compositions with a high concentration of antifungal agent, suitable for application to the nail - Google Patents
Method of dissolving antifungal agent, and compositions with a high concentration of antifungal agent, suitable for application to the nail Download PDFInfo
- Publication number
- WO2010100252A1 WO2010100252A1 PCT/EP2010/052817 EP2010052817W WO2010100252A1 WO 2010100252 A1 WO2010100252 A1 WO 2010100252A1 EP 2010052817 W EP2010052817 W EP 2010052817W WO 2010100252 A1 WO2010100252 A1 WO 2010100252A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- water
- pharmaceutical composition
- antifungal agent
- terbinafine
- composition according
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Definitions
- the present invention relates to the development of a ternary solvent system comprising water that allows substantial amounts of antifungal agents from the class of the allylamines or from the class of the morpholines to be dissolved.
- This invention allows compositions to be prepared that are specifically adapted to application to the nail, the latter possibly being optionally perforated or pretreated chemically or physically.
- Pharmaceutical or dermatological compositions of this kind are useful especially for the treatment, in humans and animals, of onychomycoses, especially those due to dermatophytes or to Candida.
- Antifungal agents from the class of the allylamines, especially terbinafine or naftifine, and those from the class of the morpholines, especially amorolfine, are promising compounds in antifungal control. Their presumed or demonstrated mode of action involves inhibition at the level of ergosterol, a specific constituent of the wall of fungal cells, especially via the inhibition of squalene epoxidase ("Terbinafine: Mode of action and properties of the squalene epoxidase inhibition" British Journal of Dermatology, Volume 126 Issue s39, pages 2-69 (February 1992); "Preclinical data and mode of action of amorolfine", Dermatology, 1992, vol. 184, SUPl (10 ref . ) , pp. 3-7) . Traditionally, antifungals have been administered either topically or orally.
- terbinafine administered at a level of 250 mg/day for 6 months has proved to be effective and of low toxicity in the treatment of onychomycoses due to Trichophyton rubrum.
- treatment of this kind raises a problem of duration and of cost, and sometimes has side-effects affecting the digestive sphere, taste disorders or else transitory skin eruptions (GUPTA A, LYNDE C, LAUZON G et al . Cutaneous adverse effects associated with terbinafine therapy: 10 case reports and a review of the literature. Br J Dermatol, 1998, 138: 529-532) .
- transungual administration represents an alternative solution to oral administration for the treatment of onychomycoses.
- the problem which arises in the case of administration to the nail is to ensure the penetration and spreading of the antifungal agents in the nail, allowing therapeutically effective concentrations to be attained in the nail and under the nail, in other words in the nail bed.
- the nail as such is composed essentially of keratin, a fibrous protein which is indeed insoluble yet which exhibits an affinity for water.
- the nail is considered to be hydrophilic in nature, which is to say that it behaves as a hydrogel. Consequently, and for transungual application, it would appear mandatory to formulate the antifungal agent in water.
- Water however, has difficulties in its compatibility with the aforementioned antifungal agents of interest, especially terbinafine, which per se exhibit little spreading ability into the nail, and, moreover, are virtually insoluble in water.
- the solution used has been that of an aqueous-alcoholic mixture with addition of polymers.
- document EP 0 503 988 proposed admixing the aqueous-alcoholic medium with hydrophilic penetrants, which were hitherto known and used for promoting the transcutaneous penetration of active agents through the horny layer of the skin; this horny layer is lipophilic in nature and behaves as a water barrier .
- the present invention lies in the demonstration of a ternary solvent system which comprises water and which combines a capacity for substantial amounts of antifungal agents of interest to be dissolved, the possibility of a large amount of water, and a capacity for effective spreading and effective penetration into and through the keratinized ungual tablet of the nail.
- large amount of water is meant a total amount of water in the composition of more than 30% by weight, relative to the total weight of the composition.
- the present invention provides a dermatological composition intended for the treatment of onychomycoses, which takes the form of a solution and comprises: first, an effective amount of at least one antifungal agent; second, a solvent medium for said antifungal agent (or agents) that is composed of a mixture of water, at least one branched or straight chain C2-C8 alkanol, and at least one glycol that has free hydroxyl functions.
- a composition of this kind is characterized in that the total water represents more than 30% by weight, relative to the total weight of the composition
- an "effective amount" of at least one antifungal agent is a substantial amount of said agent in the composition. It is obvious that the problem of solubility in the solvent medium, more particularly in water, arises for substantial amounts of this kind.
- the substantial amount of antifungal agent represents more than 5%, or even at least 8%, or, indeed, even at least 10% (w/w) of the total composition. Hence it is possible to envisage up to 15% or even 20% of this agent in the composition .
- the antifungal agents of interest that are more particularly a target of the present invention are those from the class of the allylamines and from the class of the morpholines, the class of the allylamines being preferred.
- terbinafine and its acid salts preference will be given to terbinafine hydrochloride and naftifine hydrochloride, the respective formulae of which are as follows:
- Naftifine hydrochloride Among the molecules from this class, preference is given to terbinafine.
- the antifungal agent may belong to the class of the morpholines, especially amorphine and its acid salts, for which similar problems of solubility in water arise.
- the invention is based on the demonstration of a ternary solvent system comprising water and exhibiting a synergy in the dissolution of the antifungal agents of interest.
- This system comprises: water, which is known to be a very poor solvent of antifungal agents from the class of the allylamines or from that of the morpholines; - a short chain alcohol, and more specifically, at least one branched or straight chain C2-C8 alkanol, these alcohols being known to be solvents for antifungal agents from the class of the allylamines or from that of the morpholines; at least one glycol.
- a very poor solvent is a solvent which allows dissolution of not more than 1% (w/w) of the antifungal agent from the class of the allylamines or from that of the morpholines.
- the total water represents more than 30% by weight, relative to the total weight of the composition (w/w) , advantageously more than 33%, or even more than 35% or, indeed, even more than 40%. Consequently, the total water advantageously represents more than a third of the ternary solvent mixture.
- total water is meant the amount of water introduced as such into the composition, with the addition of the amount of water originating from the various solvents and/or excipients in the composition, where they contain water.
- the total water represents advantageously less than 60%, or even less than 50%, of the total composition.
- the second entity in this ternary system is a short chain alcohol, and more specifically at least one branched or straight chain C2-C8 alkanol, preferably ethanol, isopropanol and n-butanol. Ethanol is particularly preferred. A mixture of different alcohols may also be contemplated.
- this ternary solvent system comprises at least one glycol.
- a glycol here is a compound which has at least two hydroxyl functions.
- the invention relates more particularly to glycols whose two hydroxyl functions are free, which is to say that they are not engaged in an ether or ester linkage.
- Such glycols include, for example, propylene glycol, butylene glycol, hexylene glycol, ethylene glycol and polyethylene glycols. Propylene glycol is preferred.
- a mixture of different glycols may also be contemplated.
- the ternary solvent system represents at least 60%, or even 70%, 80%, or, indeed, even 90% (w/w) of the total
- the proportion of alcohol is greater than or equal to that of glycol. Even more advantageously, the total proportion of water is greater than that of glycol.
- a pharmaceutical or dermatological composition according to the invention takes the form of a solution. It may equally be formulated as a lotion, spray, emulsion, foam or gel, which advantageously is fluid.
- composition according to the invention may also include at least one additive selected from the group consisting of: preservatives, such as phenylethyl alcohol, benzyl alcohol and phenoxyethanol, parabens and derivatives; antioxidants, such as butylated hydroxyanisole (BHA) , butylated hydroxytoluene (BHT) , palmityl ascorbate, alpha-tocopherol and/or its esters; dyes, fillers or pigments, such as the titanium micas commonly used in the cosmetics field for producing nail varnish; - polymers capable of preventing the flow of the composition before penetration, such as, for example, alkylcellulose derivatives, especially methylcelluloses, ethylcelluloses and hydroxy- alkylcelluloses, such as those sold under the name "KLUCEL”; chelating agents such as disodium edetate (EDTA) ; emollients such as cyclomethicone; antiseptics, especially acetic acid or chlorhex
- composition according to the invention is particularly adapted for the treatment of onychomycoses transungually . Hence it is intended for application to the surface of the nail.
- - antifungal agent terbinafine hydrochloride (terbinafine HCl)
- water purified water
- alcohol ethanol
- glycol propylene glycol
- Terbinafine HCl is weighed out accurately into a 20 ml flask and then the solvents are added. The flask is subsequently placed, with magnetic stirring, in a chamber thermostated at 20 0 C, for 16 h. If some of the active ingredient has not dissolved, a further addition of solvent is made. The flask is then placed again, with magnetic stirring, in the thermostated chamber, for 16 h, until dissolution is complete. If this is not so, the preceding step is repeated.
- the standard range is produced by varying the injection volume of solution A, at an equivalent concentration of 4 ⁇ g/ml to 120 ⁇ g/ml .
- the visual solubility of the terbinafine HCl is 19.7% w/w, confirmed at 18.09% w/w by HPLC assay;
- the visual solubility of the terbinafine HCl is 23.3% w/w, confirmed at 20.4% w/w by HPLC assay.
- the visual solubility of the terbinafine HCl is 0.6% w/w. In the case of a binary water/ethanol mixture (50/50), the visual solubility of the terbinafine HCl is 16.7% w/w, in other words below that obtained with ethanol alone.
- the amount of water was then increased to 30% in the presence of equivalent amounts of 35% of propylene glycol and 35% of ethanol.
- the visual solubility of the terbinafine HCl is then 18.5% w/w, i.e. well above 10%, a concentration determined as being optimum in terms of the biological activity of the active principle .
- the water reduces the solubility of the terbinafine HCl. Therefore, only the combination of a ternary water/propylene glycol/ethanol mixture makes it possible to increase the solubility of terbinafine HCl. It has thus been shown that the solubility of terbinafine HCl is greater than 10% in a ternary water/propylene glycol/ethanol mixture containing at least 30% of water (Graph 1) . The solubility of terbinafine remains greater than 10% with 40% of water, with the proviso that the amount of ethanol is at least greater than or equal to that of the propylene glycol.
- compositions based on the ternary solvent system allowed various formulations to be produced, containing substantial amounts of terbinafine HCl, with no solubility problem.
- the examples below are given by way of illustration, and are not at all limitative. For each example, the formula is expressed as a function of the percent of each ingredient used as sold (1st column) .
- the formula is also expressed by taking account of the water present in each ingredient. In this case, the % corresponding to the ingredients are considered to add up to 100% (2nd column) .
- the formulations are prepared by following procedure:
- Step 1 Dissolve the hydroxytoluene in ethanol.
- Step 2 When the Butylhydroxytoluene is fully dissolved, add successively:
- Step 3 add terbinafine HCL mixture obtained in step 2.
- the physical and chemical stabilities were measured for 3 months at room temperature and at 40 0 C.
- the physical and chemical stabilities were measured for 3 months at room temperature and at 40 0 C.
- Example 3 Hydroxyethy1cellulose 0.50% 0.50%
- This ternary propylene glycol/ethanol/water mixture therefore exhibits a synergistic effect in the dissolution of terbinafine HCl in the proportions used.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Emergency Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Organic Chemistry (AREA)
- Communicable Diseases (AREA)
- Dermatology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2011009093A MX2011009093A (es) | 2009-03-06 | 2010-03-05 | Metodo para disolver agentes antimicoticos, y composiciones con una alta concentracion de agentes antimicoticos, apropiado para su aplicacion a las uñas. |
JP2011552461A JP2012519669A (ja) | 2009-03-06 | 2010-03-05 | 抗真菌剤を溶解する方法、および爪への塗布に適している、高濃度の抗真菌剤を含む組成物 |
CN2010800108976A CN102341092A (zh) | 2009-03-06 | 2010-03-05 | 溶解抗真菌剂的方法,以及含有高浓度抗真菌剂的适合施用于指甲的组合物 |
EP10707032A EP2403476A1 (en) | 2009-03-06 | 2010-03-05 | Method of dissolving antifungal agent, and compositions with a high concentration of antifungal agent, suitable for application to the nail |
US13/254,989 US20120309753A1 (en) | 2009-03-06 | 2010-03-05 | Method of dissolving antifungal agent, and compositions with a high concentration of antifungal agent, suitable for application to the nail |
RU2011140574/15A RU2011140574A (ru) | 2009-03-06 | 2010-03-05 | Способ растворения противогрибкового средства и композиции с высокой концентрацией противогрибкового средства, подходящие для нанесения на ногти |
BRPI1006666A BRPI1006666A2 (pt) | 2009-03-06 | 2010-03-05 | " composição farmacêutica e uso de uma composição farmacêutica" |
CA2753638A CA2753638A1 (en) | 2009-03-06 | 2010-03-05 | Method of dissolving antifungal agent, and compositions with a high concentration of antifungal agent, suitable for application to the nail |
AU2010220266A AU2010220266A1 (en) | 2009-03-06 | 2010-03-05 | Method of dissolving antifungal agent, and compositions with a high concentration of antifungal agent, suitable for application to the nail |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US20251609P | 2009-03-06 | 2009-03-06 | |
FR0951416 | 2009-03-06 | ||
FR0951416A FR2942716B1 (fr) | 2009-03-06 | 2009-03-06 | Methode de solubilisation d'agent antifongique et compositions a haute concentration en agent antifongique applicables sur l'ongle |
US61/202,516 | 2009-03-06 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010100252A1 true WO2010100252A1 (en) | 2010-09-10 |
Family
ID=41056884
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2010/052817 WO2010100252A1 (en) | 2009-03-06 | 2010-03-05 | Method of dissolving antifungal agent, and compositions with a high concentration of antifungal agent, suitable for application to the nail |
Country Status (11)
Country | Link |
---|---|
EP (1) | EP2403476A1 (zh) |
JP (1) | JP2012519669A (zh) |
KR (1) | KR20110121702A (zh) |
CN (1) | CN102341092A (zh) |
AU (1) | AU2010220266A1 (zh) |
BR (1) | BRPI1006666A2 (zh) |
CA (1) | CA2753638A1 (zh) |
FR (1) | FR2942716B1 (zh) |
MX (1) | MX2011009093A (zh) |
RU (1) | RU2011140574A (zh) |
WO (1) | WO2010100252A1 (zh) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9161914B2 (en) | 2013-01-31 | 2015-10-20 | Merz Pharmaceuticals, Llc | Topical compositions and methods for making and using same |
US9433680B2 (en) | 2013-01-31 | 2016-09-06 | Merz Pharmaceuticals, Llc | Topical compositions and methods for making and using same |
US9446131B2 (en) | 2013-01-31 | 2016-09-20 | Merz Pharmaceuticals, Llc | Topical compositions and methods for making and using same |
US9452173B2 (en) | 2013-01-31 | 2016-09-27 | Merz Pharmaceuticals, Llc | Topical compositions and methods for making and using same |
US20170239328A1 (en) * | 2014-10-21 | 2017-08-24 | Hexima Limited | Method of Treatment |
US10245257B2 (en) | 2013-11-22 | 2019-04-02 | Dow Pharmaceutical Sciences, Inc. | Anti-infective methods, compositions, and devices |
US10342875B2 (en) | 2013-10-03 | 2019-07-09 | Dow Pharmaceutical Sciences, Inc. | Stabilized efinaconazole compositions |
US10512640B2 (en) | 2008-01-03 | 2019-12-24 | Dow Pharmaceutical Sciences, Inc. | Compositions and methods for treating diseases of the nail |
US10828369B2 (en) | 2010-07-08 | 2020-11-10 | Dow Pharmaceutical Sciences, Inc. | Compositions and methods for treating diseases of the nail |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2587064C2 (ru) * | 2011-02-11 | 2016-06-10 | Моберг Фарма Аб | Новая противогрибковая композиция |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0503988A1 (fr) | 1991-03-08 | 1992-09-16 | Sandoz Ltd. | Compositions pour le traitement des onychomycoses |
EP0515312A2 (en) * | 1991-05-23 | 1992-11-25 | Sandoz Ltd. | Pharmaceutical composition containing terbinafine as an anti-mycotic agent |
WO2008121709A1 (en) * | 2007-03-30 | 2008-10-09 | Transport Pharmaceuticals, Inc. | Pharmaceutical formulations for iontophoretic delivery of an anti-fungal drug |
-
2009
- 2009-03-06 FR FR0951416A patent/FR2942716B1/fr not_active Expired - Fee Related
-
2010
- 2010-03-05 WO PCT/EP2010/052817 patent/WO2010100252A1/en active Application Filing
- 2010-03-05 CN CN2010800108976A patent/CN102341092A/zh active Pending
- 2010-03-05 KR KR1020117020728A patent/KR20110121702A/ko not_active Application Discontinuation
- 2010-03-05 CA CA2753638A patent/CA2753638A1/en not_active Abandoned
- 2010-03-05 RU RU2011140574/15A patent/RU2011140574A/ru unknown
- 2010-03-05 BR BRPI1006666A patent/BRPI1006666A2/pt not_active Application Discontinuation
- 2010-03-05 EP EP10707032A patent/EP2403476A1/en not_active Withdrawn
- 2010-03-05 AU AU2010220266A patent/AU2010220266A1/en not_active Abandoned
- 2010-03-05 JP JP2011552461A patent/JP2012519669A/ja active Pending
- 2010-03-05 MX MX2011009093A patent/MX2011009093A/es unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0503988A1 (fr) | 1991-03-08 | 1992-09-16 | Sandoz Ltd. | Compositions pour le traitement des onychomycoses |
EP0515312A2 (en) * | 1991-05-23 | 1992-11-25 | Sandoz Ltd. | Pharmaceutical composition containing terbinafine as an anti-mycotic agent |
WO2008121709A1 (en) * | 2007-03-30 | 2008-10-09 | Transport Pharmaceuticals, Inc. | Pharmaceutical formulations for iontophoretic delivery of an anti-fungal drug |
Non-Patent Citations (3)
Title |
---|
"Preclinical data and mode of action of amorolfine", DERMATOLOGY, vol. 184, 1992, pages 3 - 7 |
"Terbinafine: Mode of action and properties of the squalene epoxidase inhibition", BRITISH JOURNAL OF DERMATOLOGY, vol. 126, no. S39, February 1992 (1992-02-01), pages 2 - 69 |
GUPTA A; LYNDE C; LAUZON G ET AL.: "Cutaneous adverse effects associated with terbinafine therapy: 10 case reports and a review of the literature", BR J DERMATOL, vol. 138, 1998, pages 529 - 532 |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11872218B2 (en) | 2008-01-03 | 2024-01-16 | Bausch Health Ireland Limited | Compositions and methods for treating diseases of the nail |
US11213519B2 (en) | 2008-01-03 | 2022-01-04 | Bausch Health Ireland Limited | Compositions and methods for treating diseases of the nail |
US10512640B2 (en) | 2008-01-03 | 2019-12-24 | Dow Pharmaceutical Sciences, Inc. | Compositions and methods for treating diseases of the nail |
US10828369B2 (en) | 2010-07-08 | 2020-11-10 | Dow Pharmaceutical Sciences, Inc. | Compositions and methods for treating diseases of the nail |
US9433680B2 (en) | 2013-01-31 | 2016-09-06 | Merz Pharmaceuticals, Llc | Topical compositions and methods for making and using same |
US9446131B2 (en) | 2013-01-31 | 2016-09-20 | Merz Pharmaceuticals, Llc | Topical compositions and methods for making and using same |
US9452173B2 (en) | 2013-01-31 | 2016-09-27 | Merz Pharmaceuticals, Llc | Topical compositions and methods for making and using same |
US10166206B2 (en) | 2013-01-31 | 2019-01-01 | Sebela International Bermuda Limited | Topical compositions and methods for making and using same |
US10166205B2 (en) | 2013-01-31 | 2019-01-01 | Sebela International Bermuda Limited | Topical compositions and methods for making and using same |
US9161914B2 (en) | 2013-01-31 | 2015-10-20 | Merz Pharmaceuticals, Llc | Topical compositions and methods for making and using same |
US10695303B2 (en) | 2013-01-31 | 2020-06-30 | Sebela Ireland Limited | Topical compositions and methods for making and using same |
US10729667B2 (en) | 2013-01-31 | 2020-08-04 | Sebela Ireland Limited | Topical compositions and methods for making and using same |
US10342875B2 (en) | 2013-10-03 | 2019-07-09 | Dow Pharmaceutical Sciences, Inc. | Stabilized efinaconazole compositions |
US10864274B2 (en) | 2013-10-03 | 2020-12-15 | Bausch Health Ireland Limited | Stabilized efinaconazole formulations |
US10828293B2 (en) | 2013-11-22 | 2020-11-10 | Dow Pharmaceutical Sciences, Inc. | Anti-infective methods, compositions, and devices |
US10245257B2 (en) | 2013-11-22 | 2019-04-02 | Dow Pharmaceutical Sciences, Inc. | Anti-infective methods, compositions, and devices |
US11654139B2 (en) | 2013-11-22 | 2023-05-23 | Bausch Health Ireland Limited | Anti-infective methods, compositions, and devices |
US10973874B2 (en) * | 2014-10-21 | 2021-04-13 | Hexima Limited | Method of treatment |
US20170239328A1 (en) * | 2014-10-21 | 2017-08-24 | Hexima Limited | Method of Treatment |
Also Published As
Publication number | Publication date |
---|---|
AU2010220266A1 (en) | 2011-09-08 |
KR20110121702A (ko) | 2011-11-08 |
BRPI1006666A2 (pt) | 2016-04-19 |
FR2942716A1 (fr) | 2010-09-10 |
CA2753638A1 (en) | 2010-09-10 |
EP2403476A1 (en) | 2012-01-11 |
JP2012519669A (ja) | 2012-08-30 |
CN102341092A (zh) | 2012-02-01 |
RU2011140574A (ru) | 2013-04-20 |
MX2011009093A (es) | 2011-09-27 |
FR2942716B1 (fr) | 2011-04-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2010100252A1 (en) | Method of dissolving antifungal agent, and compositions with a high concentration of antifungal agent, suitable for application to the nail | |
EP2191826B1 (en) | Pharmaceutical composition | |
EP2191828B1 (en) | Antifungal pharmaceutical composition | |
EP2704703B1 (en) | Transdermal compositions of ibuprofen and methods of use thereof | |
CA3020157C (en) | Topical composition comprising tacrolimus | |
JP2555555B2 (ja) | 抗真菌性外用製剤 | |
US20120328543A1 (en) | Use of a cationic, advantageously amphoteric, surfactant for the preparation of an antifungal solution that can be applied to the nail | |
JP5033381B2 (ja) | 外用医薬組成物 | |
AU2020236525B2 (en) | Stable topical compositions of Fenoldopam | |
US20120309753A1 (en) | Method of dissolving antifungal agent, and compositions with a high concentration of antifungal agent, suitable for application to the nail | |
EP3666254A2 (en) | Pharmaceutical composition containing (r)-n-[1-(3,5-difluoro-4-methansulfonylamino-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide | |
WO2007086582A1 (ja) | 22-オキサ-1α,25-ジヒドロキシビタミンD3を含有する水中油型乳剤性ローション剤およびそれを用いた皮膚疾患の治療方法 | |
JP4060347B2 (ja) | 22−オキサ−1α,25−ジヒドロキシビタミンD3を含有する水中油型乳剤性ローション剤 | |
JP5460766B2 (ja) | 外用医薬組成物 | |
JPH111433A (ja) | トルナフテ−ト含有液剤 | |
US20240131008A1 (en) | topical formulation of Disease-Modifying Antirheumatic Drug (DMARDs) for treatment of rheumatoid arthritis, melanoma, squamous cell carcinoma, atopic dermatitis and psoriasis | |
WO2023016583A1 (zh) | 一种芦可替尼组合物及其用途 | |
EP4342449A1 (en) | Hydroalcoholic single phase gel compositions for topical delivery of diclofenac | |
EP4342450A1 (en) | Hydroalcoholic topical diclofenac formulations | |
WO2023172216A1 (en) | Hydrocortisone and pramoxine topical formulations having enhanced in-vitro release |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201080010897.6 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 10707032 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010707032 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010220266 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2753638 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2011/009093 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 3621/KOLNP/2011 Country of ref document: IN |
|
ENP | Entry into the national phase |
Ref document number: 20117020728 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011552461 Country of ref document: JP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2010220266 Country of ref document: AU Date of ref document: 20100305 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2011140574 Country of ref document: RU Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13254989 Country of ref document: US |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: PI1006666 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: PI1006666 Country of ref document: BR Kind code of ref document: A2 Effective date: 20110906 |